Visna is a slow progressive demyelinating disease of the central nervous system of sheep caused by an exogenous retravirus. Our objective is to continue and extend our studies of the pathogenesis of this disease using multidisciplinary approaches of molecular biology, virology, immunology and pathology. The proposed research will examine the mechanism of restriction of virus replication and the role of antigenic alteration of virus in the persistent infection by genetic studies of the viral genome. The concept that the protracted disease represents cumulative pathologic effects of cycles of infection caused by mutant viruses will be tested by examination of dynamic interrelationships of rates of viral synthesis and host responses during one cycle of infection. Attempts to accelerate the disease by sequential inoculation of mutant visna viruses in the same animals will also be done. Finally, the mechanisms of genetic resistance of sheep to visna will be examined by comparative studies of virus-host cell responses to infected resistant and susceptible sheep.